(a) Field of Invention
This invention relates to carba derivatives of the tetradecapeptide somatostatin. More particularly, this invention concerns carba decapeptide derivatives in which phenylalanine at position 6 is replaced with tyrosine, the L-tryptophan is replaced with D-trytophan and one or two of the sulfur atoms is replaced with a methylene group and salts thereof, a process for preparing said derivatives and salts, intermediates used in the process, compositions and methods for using the carba decapeptide derivatives and their salts.
(b) Prior Art
The name "somatostatin" has been proposed for the factor found in hypothalamic extracts which inhibits the secretion of growth hormone (somatotropin). The structure of this factor has been elucidated by P. Brazeau et al., Science, 179, 77 (1973) and reported to have the following tetradecapeptide structure: ##STR2##
The constitution of the tetradecapeptide somatostatin has been confirmed by synthesis; for example, see D. Sarantakis and W. A. McKinley, Biochem. Biophys. Res. Comm., 54, 234 (1973), J. Rivier et al., Comp. Rend., Ser. D, 276 2737 (1973) and H. U. Immer et al., Helv. Chim. Acta, 57, 730 (1974).
The important physiological activity of this tetradecapeptide established it as a compound of significance for clinical pharmacology relating to the treatment of acromegaly and the management of diabetes; for example, see K. Lundbaek et al., Lancet, 2, 131 (1970) and R. Guillemin in "Chemistry and Biology of Peptides", J. Meienhofer, Ed., 3rd American Peptide Symposium Boston 1972, Ann Arbor Science Publications, Ann Arbor, Mich., 1972.
Since the structure and physiological activity of somatostatin were determined, a number of analogs of somatostatin have been reported, for instance see the report by J. Rivier, et al., in "Peptides 1976", Editions de L'Universite de Bruxelles, Brussels, Belgium, edited by A. Loffet, 1977, pp. 427-451. More specifically, a number of decapeptide derivatives of somatostatin have been reported, for example: Derwent Publications Ltd., Farmdoc 75059X for Netherland patent application Ser. No. 7,602,395, published Sept. 14, 1976, discloses compounds of the formula ##STR3## in which X is Lys, Nle or Cys and Y is Asn, Gln or Thr; Derwent Publications Ltd., Farmdoc 70672W for Belgium Pat. No. 827,530 issued Oct. 3, 1975, discloses compounds of the formula ##STR4## in which V is Asn or Ala and W is Lys or Orn; and by H. U. Immer et al., in U.S. Pat. No. 4,020,147, issued Apr. 26, 1977, discloses compounds of the formula ##STR5## in which R is hydrogen or NHR.sup.1 wherein R.sup.1 is lower aliphatic acyl or benzoyl.
Carba decapeptide derivatives of somatostatin also are known; for example, Derwent Publications Ltd., Farmdoc 13282Y for German patent application No. 2,635,558, published Feb. 17, 1977 discloses peptides of the formula ##STR6## in which X is CH.sub.2, S or (X).sub.n wherein n is 0 and Y is CH.sub.2, S or (Y).sub.n wherein n is O; and D. F. Verber in U.S. Pat. No. 4,115,554, issued Sept. 19, 1978 discloses of the formula ##STR7## wherein R is H or COOH; A is (Asn).sub.n wherein n=0 or 1, .alpha.-Abu, Pro or Ala; B is Phe or Tyr; C and D are independently Thr or Val; and E is Ser, Pro, Ala or Gly; wherein at least one of A and E is Pro.
Furthermore, a number of somatostatin derivatives in which a phenylalanine residue is replaced by a tyrosine residue is reported by J. E. Rivier et al., J. Med. Chem., 19, 1010 (1976).
The present invention discloses novel carba decapeptide derivatives of somatostatin in which phenylalanine at position 6 is replaced with tyrosine, the L-tryptophan is replaced with D-tryophan and one or two of the sulfur atoms is replaced with a methylene group. The carba decapeptide derivatives of this invention have a favourable and important separation of the inhibition of insulin and glucagon activities. These decapeptides show a greater inhibition on the release of glucagon than on the release of insulin when compared to somatostatin. This feature makes the decapeptides of this invention especially useful for the treatment of diabetes in a diabetic mammal.
The carba derivatives of this invention are prepared readily by a convenient process, which includes the following advantages: the process starts from readily available materials, avoids noxious reagents, is executed facilely and utilizes easily removable protecting groups.